Enteric coated tablets and methods of making the same



July 26, 1955 v. M. HERMELIN ENTERIC COATED TABLETS AND METHODS OF MAKING THE SAME Filed Oct. 1l, 1954 l, 1 ipk FIG. l.

FIG. 2.

INVENTOR.

Vlcron M. HERMELIN ETERC CTED TAELETS AND METHDS 0F lt/AKNG THE SAME 9 Ciaims.

This invention relates in general to certain new and useful improvements in pharmaceutical preparations and, more particularly, to enteric coated tablets and methods of making the same. The present application is a continuation-in-part of application Serial No. 195,368, filed November 13, 1950, now abandoned.

It has been accepted practice in the compounding of pharmaceutical tablets to provide certain types of tablets with what has been commonly referred to as an enteric coating. The enteric coating is one which will resist the action of the gastric juices in the stomach and will not dissolve therein or be otherwise affected thereby so that the drug which is incorporated in the tablet will pass through the stomach and into the intestine. The socalled enteric coating is of such a nature that it will be dissolved very readily in the intestinal fluids, so that the drug which has been enclosed in the enteric coating will become etfective in the intestinal tract rather than in the stomach. The medical profession has, as a matter of fact, developed a number of types of treatments in which enteric coatings are considered to be extremely useful.

At the present time, however, the existing methods of forming enteric coatings are not particularly satisfactory and the enteric coatings now in use are not always cornpletely reliable. Actual tests with various types of enteric coatings have shown that most available enteric coatings are either dissolved in the gastric juices of the stomach or at least are attacked by such gastric juices, so that an appreciable quantity of the drug in the tablet will leak out or be transferred through the enteric coating by a process of osmosis. Frequently this is a result of transmigration of moisture picked up by the interior components of the tablet during manufacture. Where only a common water soluble sugar coating is applied tol a tablet, any moisture trapped in the slug will diffuse outwardly through the coating as it is built up. An enteric coating, however, tends to seal in any trapped moisture and during normal shelf-life such moisture bursts through the coating forming damp spots on the tablet surface and riddling the coating with almost microscopically small channels or bleed holes through which gastric juices can attack the slug while the tablet is in the stomach. Such deficiencies, in addition to permitting the drugs in the slug to leak out, so to speak, in the stomach also may result in the serious deterioration in physical strength of the enteric coating, so that the tablet will collapse under the peristaltic action of the stomach. Obviously, such enteric coatings are completely ineffective because the drug, which is compounded in the tablet, will become effective in the stomach Where it is not supposed to be effective or will become effective at a time much earlier than that planned for the dosage. In either case, the result is entirely unsatisfactory.

It is the primary object of the present invention, therefore, t0 provide a pharmaceutical tablet having a unique and novel enteric coating which will not be affected by the gastric juices in the stomach and will not, in any way, permit osmotic dilution of the tablet when in the stomach.

It is also an object of the present invention to provide a pharmaceutical tablet having an enteric coating which is impervious to moisture trapped within the tablet-slug during manufacture or tending to difliuse inwardly into the tablet-slug due to humidity or similar conditions to which the tablet is subjected after manufacture.

It is another object of the present invention to provide a pharmaceutical tablet which is enclosed within a coating that will travel through the stomach of the patient into the intestinal tract and be positively, speedily, and surely disintegrated in the intestinal tract, so that the full therapeutic effect of the drug contained in the tablet will be rendered active in the intestinal tract.

It is also an object of the present invention to provide methods of making the enteric coated tablets which are impervious to moisture, will not dissolve in the patients stomach and will not become moisture-spotted or moisture-channeled during storage.

It is a further object of the present invention to provide a pharmaceutical tablet having a unique and novel enteric coating which is simple and precise in its action and is economical to produce.

With the above and other objects in view, my invention resides in the novel features of form, construction, arrangement, and combination of parts presently described and pointed out in the claims.

in the accompanying drawing- Figure l is a transverse sectional View of a pharmaceutical tablet embodying the present invention; and

Figure 2 is a transverse sectional View of a modied form of pharmaceutical tablet embodying the present invention.

Referring now in more detail and by reference characters to the drawing, which illustrates practical embodiments of the present invention. A designates a pharmaceutical tablet which comprises a spherical slug or core lt formed by compressing a properly granulated mixture of drugs and other tablet ingredients in a conventional tableting machine having appropriately shaped punches of the desired design. A suitable number of slugs or cores 1 are placed in a conventional coating pan and the coating pan set into rotation. Thereupon, a quantity of confectioners glaze or other similar binding agent is poured into the coating pan in sutiicient amount to cover all of the slugs l with a thin, but nevertheless complete,

' liquid coating. Thereupon, a finely pulverized desiccant,

such as anhydrous silica gel, is dusted into the coating pan until the liquid coating is thoroughly dried up, so to speak, that is to say, the iilm of glaze on each core 1 is completely covered with the silica gel to form an initial covering layer 2. As soon as the layer 2 has been completely formed, the addition of silica gel is stopped and the coating pan allowed to continue its rotation until the alcohol in the glaze has fully evaporated. Thereupon, a quantity of castor oil is poured into the coating pan in a suiiicient amount to form a thin film upon each slug 1.

When this has been accomplished, finely pulverized stearic acid is dusted into the coating pan in sufcient amount to completely dry up the lm of castor oil and thereby form a second enclosing layer 3. When this layer v3 has been completely formed, the addition of stearic acid is stopped and the coating pan allowed to run :for a second compacting period of approximately one-half hour in duration, so that the layer 3 will become thoroughly compacted and densified by the mechanical action of the tablets rolling one upon the other or tumbling as it is sometimes called.

Then, more castor oil is poured into the coating pan in sucient quantity to form a relatively heavy moist lm of castor oil around each coated slug 1. In this instance,

a somewhat greater amount of castor oil is preferablyi employed, so that the liquid coating formed on the partially coated core will be somewhat thicker than the two previous films. As soon as the addition of castor oil has hour, whereupon the three coating layers 2, 3, 4, will i' be found to be thoroughly compacted and of a very dense physical structure as compared with enteric coatings formed by conventional processes.

Finally, an exterior sugar coating 5 is conventionally applied, thereby completing the tablet A.

By Way of illustration and not for purposes of limitation, the following are examples of various types of medicinal tablets made in accordance with the present invention:

Example I Ammonium chloride gr./tablet 5 Approximately 70 pounds of ammonium chloride U. S. P. is processed through a tableting machine tted with suitable punches and dies to form 5 gr. tablets. The slugs or cores thus formed are placed in a coating pan and the initial coating or layer 2 is formed by gradually applying approximately 24 to 30 ounces of confectioners glaze and 6 pounds of inely pulverized silica gel. Actually, the coating is carried out, as hereinabove stated, by a process of forming a wet lm and then dusting in silica gel to dry up the lilm. This can be controlled by visual observation since the wet film has a shiny appearance, but when the lilm is thoroughly dry, it is visually apparent that the shininess is completely gone and additional powder no longer appears but begins to form a dusty powder-layer in the coating pan. At this point, the addition of powdered silica gel is stopped. Thereupon, the coating layers 3, 4, are formed by using approximately l2 ounces of castor oil and l2 pounds of powdered stearic acid in substantially the same manner as previously described in connection with the formation of the silica gel coating or layer 2. Thereafter, the final or outer layer 5 is formed by the application of approximately l0 to 12 ounces of a conventional sugar coating.

Example Il Ferrous sulfate gr./tablet 5 Coated as per Example I.

Example III The appropriate amounts of stilbesterol and lactose are mixed in a mixer in the above proportions and tableted to provide the compressed slugs or cores 1 each containing 5 gr. of stilbesterol and 2 gr. of lactose, the latter being a ller. The cores or slugs thus made are then coated in the same manner as described above in conncction with Example I.

Example V Sodium salycilate gr./tablet 4 Sodium para-aminobenzoate gr./tablet 4 Ascorbic acid mg/tablet" 20 The appropriate amounts of sodium salycilate, sodium para-aminobenzoate, and ascorbic acid are mixed in a mixer in the above proportions and tableted to provide the compressed slugs or cores l each containing 4 gr. of sodium salycilate, 4 gr. of sodium para-aminobenzoate,

and 20 mg. of ascorbic acid. The cores or slugs thus made are then coated in the same manner as described above in connection with Example I.

Example VI Aminopnylline gr./ tablet- 3 Dicalcium phosphate gr./ tablet-- 1/2 The appropriate amounts of aminophylline and dicalcium phosphate are mixed in a mixer in the above proportions and tableted to provide the compressed slugs or cores i each containing 3 gr. of aminophylline and 1/2 gr. of dicalcium phosphate, the latter being a ller. The cores or slugs thus made are then coated in the same manner as described above in connection with Example I.

Example VII Aminophylline gr./tablet 11/2 Ephedrine gr./tablet Phenobarbital gn/tablet-- ls The appropriate amounts of aminophylline, ephedrine, and phenobarbital are mixed in a mixer in the above proportions and tableted to provide the compressed slugs or cores l each containing 1% gr. of aniinophylline, 3/s gr. of ephedrine and 1/s gr. ot' phenobarbital. The cores or sings thus made are then coated in the same manner as described above in connection with Example l.

Example VIII Bile salts (dried ox gall) gt /tablet-- 5 Coated as per Example I.

if desired, it is possible to form an oblate-cylindrical type of tablet B, such as that shown in Figure 2, by form ing a slug or core 6 in a tableting machine equipped with punches having the conventional oblate-cylindrical contour. The slug or core 6 may, of course, be of any desired size depending upon the drug used and the dosage desired. A suitable quantity of oblate-cylindrical slugs or cores 6 are placed in a conventional coating pan and provided with an initial layer 7 of anhydrous silica gel and two densely compacted successive castor oil-stearic acid layers 8, 9, exactly in the manner previously described, and, if desired, a final exterior coating l0 is applied.

The tablets A and B have been found to be entirely resistant and impervious to the action of the gastric juices in the stomach and will uniformly and invariably pass completely through the stomach of the patient into the intestinal tract. It will, of course, be understood that the outer sugar glaze coating will dissolve in the stomach, but this, of course, is of no importance since the sugar glaze coating is employed primarily to render the tablet attractive in appearance and palatable to the taste of the patient. The tablets A and B, which are substantially identical in all medical respects, diiering from each other only in physical contour, will pass into the intestinal tract minus the outer sugar glaze coating and immediately upon reaching the intestinal tract will begin to disintegrate so that the drugs or medicinal agents incorporated within the core of the tablet will become etfective in the intestinal tract within approximately live to ten minutes after reaching the intestinal tract. The entire tablet will become dissolved in the intestinal tract Within a period of less than thirty minutes. It has been found that no tablets were eliminated with the intestinal excretion.

It should be understood that changes and modifications in the form, construction, arrangement, and combination of the several parts of the enteric coated tablet and methods of making the same may be made and substituted for those herein shown and described Without departing from the nature and principle of my invention.

Having thus described my invention, what I claim and desire to secure by Letters Patent is:

l. A method of making a pharmaceutical tablet which comprises forming a compact drug-containing core,

placing a plurality of such cores in a coating pan and rotating the pan, forming an initial coating on the tablet by the introduction of an adhesive and anhydrous silica gel, tumbling the coated cores for a period of time to compact said initial coating, subsequently forming an outer coating on the tablet by introducing into the coating pan castor oil and stearic acid, and tumbling the tablets for a period of time after the second coating has been formed to compact such second coating.

2. A pharmaceutical tablet comprising a drug-containing compressed core, a first coating layer disposed entirely around the exterior surface of the core, said rst coating layer consisting of pulverized anhydrous silica gel and coniectioners glaze, and a plurality of successive separately applied outer layers disposed entirely around the outer surface of the first coating layer and, in turn, around the outer surfaces of each preceding layer, said outer coatings consisting of castor oil and stearic acid.

3. A pharmaceutical tablet comprising a drug-containing compressed core, a moisture-barrier adhesive coating layer containing finely pulverized anhydrous silica gel, said coating layer being disposed entirely around and completely enclosing the core, a first enteric coating consisting of stearic acid and castor oil, said first enteric coating extending around and entirely enveloping the outer surface of the moisture-barrier coating, and a second enteric coating consisting of stearic acid and castor oil, said second enteric coating extending around and entirely enveloping the outer surface of the first enteric coating.

4. A pharmaceutical tablet comprising a drug-containing compressed core, a moisture-barrier adhesive layer coating containing finely pulverized anhydrous silica gel, said layer being disposed entirely around and completely enclosing the core, a first enteric coating consisting of stearic acid and castor oil, said first enteric coating extending around and entirely enveloping the outer surface of the moisture-barrier coating, and a second enteric coating consisting of stearic acid and castor oil, said second enteric coating extending around and entirely enveloping the outer surface of the rst enteric coating, said second enteric coating, furthermore, being substantially thicker than the rst enteric coating.

5. A pharmaceutical tablet comprising a drug-containing compressed core, an initially applied coating layer disposed entirely around the surface of the core, said initially applied coating layer containing nely pulverized anhydrous silica gel, and a subsequently applied coating layer disposed entirely around the outer surface of the initially applied coating layer, said subsequently applied coating layer being an enteric coating.

6. A pharmaceutical tablet comprising a drug-containing compressed core, an initially applied coating layer disposed entirely around the surface of the core, said 6 initially applied coating layer containing anhydrous silica gel, and a subsequently applied coating layer disposed entirely around the outer surface of the initially applied coating layer, said subsequently applied coating layer containing castor oil and stearic acid.

7. A pharmaceutical tablet comprising an internal compressed core containing a substantially dry medication, a dry barrier layer disposed upon the outer surface of the core and entirely enveloping it, said dry barrier layer consisting of an initially adhesive film throughout which dry pulverized silica gel is dispersed and retentively bound, and an external enteric coating disposed upon and completely enveloping the outer surface of the dry barrier layer.

8. A pharmaceutical tablet comprising an internal compressed core containing a substantially dry medication, a dry barrier layer disposed upon the outer surface of the core and entirely enveloping it, said dry barrier layer consisting of an initially adhesive film throughout which dry pulverized silica gel is dispersed and retentively bound, and an external enteric coating disposed upon and completely enveloping the outer surface of the dry barrier layer, said coating consisting of castor oil and stearic aicd.

9. A pharmaceutical tablet comprising an internal compressed core containing a substantially dry medication, a dry barrier layer disposed upon the outer surface of the core and entirely enveloping it, said dry barrier layer consisting of an initially adhesive film throughout Which dry pulverized silica gel is dispersed and retentively bound, and an external enteric coating disposed upon and completely enveloping the outer surface of the dry barrier layer consisting of a plurality of densely com pacted layers of castor oil and stearic acid. l

References Cited in the tile of this patent UNITED STATES PATENTS 2,146,867 Welin Feb. 14, 1939 2,373,763 Kuever Apr. 17, 1945 2,512,192 Yen June 20, 1950 FOREIGN PATENTS 461,317 Great Britain Feb. 8, 1937 228,940 Great Britain June 9, 1926 109,438 Australia Jan. 11, 1940 533,625 Great Britain Feb. 17, 1941 OTHER REFERENCES Merck Index, 4th ed., p. 312 (1930).

Jour. Amer. Pharm. Assn. (Pharm. Abs.), p. 106, April 1942.

Jour. Amer. Pharm. Assn. (Pharm. Abs.), p. 105, April 1944.

Jour. Amer. Pharm. Assn., Sci. Ed., May 1945, pp.

55 13S-142; pp. 135 and 136 pertinent. 

5. A PHARMACEUTICAL TABLET COMPRISING A DRUG-CONTAINING COMPRESSED CORE, AN INITIALLY APPLIED COATING LAYER DISPOSED ENTIRELY AROUND THE SURFACE OF THE CORE, SAID INITIALLY APPLIED COATING LAYER CONTAINING FINELY PULVERIZED ANHYDROUS SILICA GEL, AND A SUBSEQUENTLY APPLIED COATING LAYER DISPOSED ENTIRELY AROUND THE OUTER SURFACE OF THE INITIALLY APPLIED COATING LAYER, SAID SUBSEQUENTLY APPLIED COATING LAYER BEING AN ENTERIC COATING. 